The thymus plays a critical role in the maturation and production of T lymphocytes and is a target of infection for human immunodeficiency virus (HIV). To examine early effects of infection on the thymus and the influence of nef, we infected macaques with either pathogenic (SIVmac239) or nonpathogenic nef-deleted (SIVmac239 nef) molecular clones of SIV and examined the distribution and immunophenotype of infected cells and performed morphometric analyses of cell proliferation and apoptosis during the first 50 days of infection. While both viruses infected the thymus, only SIVmac239 induced significant changes in cell proliferation, apoptosis and marked shifts in the percentages of T cell precursors in the thymus. Furthermore, these changes occurred coincident with peak viral loads suggesting a casual relationship.